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Genetic interrogation of conserved follicular factors for matrix metalloproteinase regulation and ovulation

Award Number: R01HD086175
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Genetic interrogation of conserved follicular factors for matrix metalloproteinase regulation and ovulation - DESCRIPTION (provided by applicant): Follicle rupture is the final step of the complex ovulation program, which releases fertilizable oocytes. Despite intensive study in the past four decades, a comprehensive understanding of the molecular mechanisms of follicle rupture is still lacking, in part due to the limitation of mammalian model systems to utilize genetic screens. We recently developed a novel Drosophila system that allows rapid application of genetic approaches to reveal precise details regarding the molecular events of follicular rupture. Moreover, recent studies from our lab have shown that the basic cellular and molecular mechanisms of ovulation are highly conserved from flies to humans; for instance, both systems require matrix metalloproteinase (Mmp) activity for follicle rupture. Leveraging the wealth of genetic tools and our ex vivo ovulation assay, this project will systematically interrogate conserved factors that are required for the precise regulation of Mmp activity and follicle rupture Our preliminary data reveals that an increase in intracellular free Ca2+ is required for Mmp activation but not expression. Conversely, follicular NADPH oxidase (Nox), which generates reactive oxygen species (ROS), and the oxidative stress-induced c-Jun N-terminal kinase (JNK) pathway regulate spatiotemporal Mmp protein expression. Therefore, we propose to 1) elucidate the conserved calcium-dependent signal transduction pathways that are required for Mmp activation, 2) investigate the role of follicular ROS and JNK signaling in Mmp expression, and 3) identify novel follicular factors for Mmp regulation and ovulation using genetic screens. This work will provide a comprehensive understanding of the ovarian signaling networks that precisely regulate Mmp activity and follicle rupture, which would be difficult in mammalian model systems. The conserved nature of these signaling pathways will allow the knowledge gained from this study to be further validated in mammalian and human ovulation. Therefore, this work will ultimately reveal promising new drug targets for the alleviation of anovulatory infertility orfor contraceptive development, both of which are highly relevant to human health.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2020	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	000	5	12/5/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	000	5	1/25/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $334,284 )
2020	2020	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	000	5	3/2/2020	NON-COMPETING CONTINUATION	$334,284
														Subtotal = $334,284

Issue Date FY: 2019 ( Subtotal = $334,571 )
2019	2019	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	000	4	2/26/2019	NON-COMPETING CONTINUATION	$334,571
														Subtotal = $334,571

Issue Date FY: 2018 ( Subtotal = $334,840 )
2018	2018	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	001	3	4/26/2018	NON-COMPETING CONTINUATION	$33,485
2018	2018	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	000	3	2/23/2018	NON-COMPETING CONTINUATION	$301,355
														Subtotal = $334,840

Issue Date FY: 2017 ( Subtotal = $335,095 )
2017	2017	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	001	2	6/14/2017	NON-COMPETING CONTINUATION	$33,510
2017	2017	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	000	2	2/22/2017	NON-COMPETING CONTINUATION	$301,585
														Subtotal = $335,095

Issue Date FY: 2016 ( Subtotal = $326,366 )
2016	2016	UNIVERSITY OF CONNECTICUT	438 WHITNEY ROAD EXTENSION	STORRS	CT	06269	CAPITOL	USA	Child Health and Human Development Extramural Research	000	1	5/3/2016	NEW	$326,366
														Subtotal = $326,366

Grand Total All Awards = $1,665,156

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Genetic interrogation of conserved follicular factors for matrix metalloproteinase regulation and ovulation

Award Number: R01HD086175

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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